Suppositorium containing insulin



April 10, 1945. a B A. BRAHN 2,373,625

SUPPOSITORIUM CONTAINING INSULIN Filed April 28, 1937 2 Sheets-Sheet 2BLOOD SUGAR m m, PER cu '2 I W y 0 f 2 a nouns I I I INVENTOR BENNOBENJAMIN ADULF 'BRAHN v BMMQQZ, 9%.

AT TORN 5Y5 Patented Apr. 10, 1945 2,373,625 SUPPOSITORIUM CONTAININGINSULIN lienno Benjamin Adolf Brahn,

sne assignments, to Ruerlands, assignor, by me chelle, N.

Amsterdam, Nethdolph Eric Victor Roesler de Villiers, New Ro-Appllcation April 28, 1937, Serial No. 139,438 In the Netherlands July28, 1936 11 Claims. (Cl. 167-64) Up to the present it has only beenpossible to introduce insulin into the human system by means ofinjections, and not by way of the stomach or the intestinal tract. Inthe latter two cases the insulin was very soon renderedinactive by thepeptic and tryptic enzymes, so that this treatment could not be appliedincases of diabetes.

It has now been found that insulin may be successfully administered inthe form of suppcsitoria, provided certain substances producing afavorable effect on the resorption of the insulin are added.

The present invention relates to suppositoria containing besides theinsulin and a substance serving as a carrier, a small proportion ofacid. This acid will either neutralize or greatly reduce theinactivating action on the insulin by the intestinal ierments, so thatby administering the said insiilin suppositoria the sugar content of the"-blood is materially reduced.

Various materials may be used as carriers for the insulin and theadditional substances. For this purpose use is preferably made ofsubstances that will melt in the intestine, such as a carrier materialor vehicle conventionally used for making suppositories, or which willdissolve in the contents of the intestine at body temperature,

such as e. g. fats having a low melting point. soaps, glycerol soaps,agar-agar, gelatine and the like. Very suitable for the purpose iscocoa-butter which is very consistent, but nevertheless will melt at atemperature of 31-32 C.

Suitable organic acids are lactic acid, citric acid or tartaric acid.For supposltoria on cocoabutter basis the, addition of higherfattyacids,

invention is illustrated in Fig. 1, which shows the results of testsmade on rabbits. In thisgraph the ordinates represent the sugar contentof the blood, the abscissae the time elapsed since the administration ofthe suppositoria. The curves indicating the blood sugar content afterdifferent intervals are averages of several determinations.

Curve 1 shows the results of a test in which suppositoria consisting of1.5 grams of cocoa-butter and units of insulin were administered. Thiscurve clearly shows that the said suppositoria do not reduce the sugarcontent of the blood.

Curve 2 relates to suppositoria containing 1.5 grams of cocoa-butter, 15units oi insulin and 0.0625 gram of lactic acid. These suppositoria havea considerable reducing influence on the sugar content of the blood, thesaid sugar content going down to approximately of its original value andreturning to the said value only after a period of about 2 hours.

A still better eiiect will be obtained when the suppositoria alsocontain saponin. This is shown by curve 3 showing the results of test inwhich suppositoria comprising 1.5 grams of cocoa-butter, 15 units ofinsulin, 0.0625 grams of lactic acid and 0.05 gram of guajac saponin,were used.

such as e. g. palmitic acid or oleic acid, etc., is

also very suitable.

' It is true that palmitic acid has amelting point of 60-62" (3., but amixture of 85 parts by weight of cocoa-butter and 15 parts by weight ofpalmitic acid will melt at 'approx'. from 33-34 C., i. e. below bodytemperature. With mixtures of cocoabutter and 15% of palmitic acid andsmall quantitles of lactic or citric acid excellent results have beenobtained in practice.

The favorable action of the. insulin suppositoria containing an organicacid may be further improved by the addition of non-haemolytic actingsaponins. Guajac saponin, the saponin of hippocastanum and glycyrrhizinehave .proved very satisfactory for this purpose. They have a favorableeflect on the resorption of the insulin in the intestines.

The effect 0! the suppositoria according to the Similar results wereobtained with healthy humans. Fig. 2 represents the curves for the sugar1 content of the blood after the administration of suppositoriaaccording to the invention having the following composition:

Curvei Cocoa-butter ..gram 1.0 Insulin units 120 Lactic acid ram" 0.15Citric. acid I do 0.1 Palmitic acid do 0.18 Guajac saponin do 0.8

Curve 2 Cocoa-butter grams 1.2 Insulin "units" 90 Lactic acid gram 0.1Saponin of hippocastanum do 0.05

Curve 3 J Cocoa-butter grams 1} Insulin -units 90 Lactic acid cram" 0.1

both organic acid and a non-haemolytic saponin.

In comparison with subcutaneous. intramuscular and intravenousadministration of insulin, the use of insulin suppositoria not only hasthe advantage that the latter are far less objectionable in the long runthan injections, but also that the preparations used may be less pure.Various substances which may be harmful in the first case, such as e. g.foreign albumens, may be present in the suppositoria. without the leastdanger.

' I claim.

1. An insulin suppository for rectal administration comprising insulin,a solid carrier of the group of materials conventionally used for makingsuppositories, a substantially non-toxic and non-irritating weak organicacid of the type of lactic acid, citric acid and tartaric acid inquantity sufllcient by its acidity to protect the insulin againstinactivating ferments in the intestines, and a non-haemolytic saponinsurface tension reducing agent.

2. A suppository as defined in claim 1 in which the carrier is cocoabutter.

3. A suppository as defined in claim 1 in which the acid is lactic acid.

4. A suppository as defined in claim 1 comprising a plurality or acidsof the group named.

5. A suppository as defined in claim 1 in which the carrier is cocoabutter and the suppository also contains a higher fatty acid.

6. A suppository as defined in claim 1 in which the carrier is cocoabutter and the suppository also contains palmitic acid.

7. A suppository as defined in claim 1 in which asraeao the carrier iscocoa butter, the acid is lactic acid, and the suppository also containspalmitic acid.

8. A suppository as defined in claim 1 in which the carrier is cocoabutter, and the suppository comprises lactic acid, citric acid andpalmitic acid.

9. A suppository containing insulin, a solid carrier of the group ofmaterials conventionally used for making suppositories and a.substantially nontoxic and non-irritating organic acid in quantitysuflicient by its acidity to protect the insulin against inactivatingferments in the intestines, said acid being present in quantityinsufficient' to exert a noxious effect upon the mucous membrane of theintestine.

10. A suppository containing insulin, a solid carrier of the group ofmaterials conventionally used for suppositories and an acid, said acidbeing present in quantity sufflcient by its acidity to protect theinsulin against inactivating ferments in the intestines and in quantityinsufficient to exert a noxious toxic or irritating effect upon themucous membrane of the intestine.

11. A suppository comprising insulin, a solid carrier of the group ormaterials conventionally used in making suppositories, an acid which inthe quantity present by its acidity protects the insulin againstinactivating ferments in the intestine and is innocuous to the mucousmembrane of the intestine, and a non-haemolytic surface tension reducingagent which promotes the absorption of the insulin through the intestinewall.

BENNO BENJAMIN ADOLF BRAHN.

